Imaging-guided BNCT applications: from physics to biology ... · Photochemical &...

Imaging-guided BNCT applications: from

physics to biology and medicine

Laura Evangelista MD, PhD Oncological Institute of Veneto IOV – IRCCS, Padova, Italy

Legnaro 15.04.2014

Multidisciplinary approach

BNCT

Physicists

Chemists

Clinicians

Biologists

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

Background

The critical requirements for a successful BNCT treatment are mainly:

(a) The boron-containing compound/material has to be delivered to the

neoplastic tissue to realize a specific and selective tumor targeting, and

(b) The amount of 10B atoms concentrated inside/around the cancer cells must

be sufficient for the therapeutic purpose.

If these rather stringent conditions are met, then irradiation of a given tissue or

organ with therapeutic doses of thermal/epithermal neutrons can lead to a

selective, complete ablation of malignant cells.

10B 7Li

n 4He

γ

……superior than conventional RT

BNCT is a biologically-

targeted radiotherapy, and

contrary of the traditional

radiotherapy, it can selectively

hit the tumour cells, saving

the surrounding normal

tissue.

4D

D

health

tumour

Health cells with boron

H),n(H 21

C)p,n(N 1414Bppm 10 30

Tumoural cells with boron

710 Li),n(B

Inib

itio

n o

f ce

ll p

rolif

era

tio

n

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

Boron delivery agent-

characteristics

The most important requirements are:

• Low toxicity

• Low uptake in normal tissue

• Tumour:normal tissue and tumour:blood ratio of ~ 3 and 2

• Tumour boron concentration of ~20 µg 10B per g of tumour

• Relatively rapid clearance from blood and normal tissue and

persistence in tumour during neutron irradiation

BSH BPA

Boron delivery agents

The most employed

New molecules

under investigation

Boronated unnatural

amino acids

Carboranyl nucleosides

Dodecaborate cluster

lipids and cholesterol

derivates

Boronated phorphyrins

Boron containing

immunoliposomes and

liposomes

Boronated EGF and anti-

EGFR and VEGFR

MoAbs

Boronated DNA

intercalators

Boron-containing

nanoparticles

Transferrin-polyethylene

glycol liposomes

Carboranyl porphyrazines

Dodecahydo-closo-

dodecaborate clusters

Boronated cyclic peptides

and nitride nanotubes

BSH BPA

ZnB4Pc H2TCP TPFC

Phtalocianine Phorphyrins Chlorine

Photochemical & Photobiological Sciences 5 (2006) 39-50

Journal of Photochemistry and Photobiology B: Biology 68 (2002) 123-132

Organic & Biomolecular Chemistry 6 (2008) 3732-3740

Department of Biology, University of Padua, Italy

Boron delivery agents

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

Dosimetry of epithermal neutron

beams

• Complicated by protons and fase neutron

components different biological effectiveness

• Multiplicative weighting factors RBE

Physicists

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

Treatment planning in a patient with GBM

The prescription dose is a

mean brain dose of 7.7 Gy.

The integral dose volume

histograms report dosimetry

of interest including target

volume and organs at risk.

Imaging-guided BCNT treatment

MRI-magnetic resonance imaging PET-positron emission tomography

From BPA to 18F-BPA for PET

imaging

PET- guided BNCT planning

©Turku PET Centre, Univ. of Turku, Finland

http://www.turkupetcentre.fi/

CT MRI [18F]F-BPA PET

Gross tumour volume : 87 cm3

Planning target volume : 233 cm3

The prognostic significance of the metabolic

values and ratios of 18F-10B-BPA by PET in

patients with gliomas.

Experimental Design: 22 patients underwent

an 18F-10B-BPA/PET study and were followed

for at least 4 months thereafter. PET

parameters, K1, k2, k3, and k4, were

measured before treatment.

Data regarding the tumors, the contralateral

normal region, and the uptake ratio of FBPA

between the tumor and normal tissue 40 min

after injection of the tracer were compared

with survival rates after the PET treatment.

A patients with recurrent submandibular gland cancer, underwent 18F-10B-BPA PET before and after BNCT.

The tumor/normal tissue boron concentration ratio was 2.9.

The tumor was irradiated at the Kyoto University Research Reactor

with epithermal neutrons 5 MW for 90 minutes.

Results. To date there has been continuous complete regression in

the tumor and no acute and chronic complications for 1.5 years.

Before BNCT After 12 mo. from BNCT

Dynamic uptake of [18F]FBPA in intracranial

meningiomas (n=4) and schwannomas (n=6) of

five sporadic and five NF2 patients. Tracer input

function and cerebral blood volume were

measured. [18F]FBPA uptake in tumour and brain

was assessed with a three compartmental model

and graphical analysis.

Conclusion: [18F]FBPA PET offers a viable

means to evaluate BPA uptake in meningiomas

and schwannomas in NF2. Meningiomas and

schwannomas might respond to low-dose BNCT

with BPA owing to their growth characteristics.

Case: a 44-yr man with recurrent poorly differentiated sinonasal

carcinoma

PRE POST

Before BNCT 2-months after BNCT

BNCT in locally recurred nasopharyngeal

cancer

Prerequisite for BNCT:

Uptake of [18F]F-BPA 2.5 ≥ surrounding normal tissue

Kankaanranta et al. Int J Radiat Oncol Biol Phys 2007;69:475-482

SUV

Scalp ◄ Brain ► ◄ Tumour ► ◄ Brain ► Scalp Nasopharyngeal cancer rT4N0

[18F]FBPA PET

Squamous cell carcinoma in the temporal

bone recurring after surgery, conventional

radiotherapy, and chemotherapy, which was

treated using planned fractionated BNCT

18F-BPA PET showed a high T/N ratio of 3.8

at the occipital condyle before the first BNCT

of squamous cell carcinoma

18F-BPA PET did not show high BPA

accumulation in the temporal in the temporal

bone at 6 months after the first BNCT

18F BPA PET/CT

CT PET PET/CT MIP

A. Wittig et al. “Boron analysis and boron imaging in biological materials for Boron Neutron

Capture Therapy (BNCT)” Critical Reviews in Oncology/Hematology 68 (2008) 66–90

Pre and post-therapy 18F-BPA PET/CT

By Prof. Ling-Wei Wang, China

Pre-BNCT

Post- BNCT

PET/CT in head-neck cancer

Pre-BNCT

Post- BNCT

By Prof. Ling-Wei Wang, China

BNCT - STEPs

Imaging Therapy

Uptake 18F-BPA

PET/CT

BSH

BPA

Others

BNCT

10B Carriers

Response to therapy

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

…from a clinical point of view Past

Pathologies

(country) N of pts Phase

GBM

(USA) 53 I-II

GBM/MM

(Germany) 26/4 I-II

GBM/AA/MRM/H&N

(Japan) 83/7/7/124 I-II

GBM/AA/H&N

(Finland) 50/2/31 I-II

GBM

(Czech Republica) 34 I-II

GBM/MM

(Sweden) 12/2 I-II

H&N

(Taiwan) 10 I

GBM: glioblastoma multifome, MM: melanoma metastasis, AA: anaplastic astrocytoma, MRM:

meningioma related malignancy; H&N: head and neck cancer

*by clinicaltrial.gov

On going*

Pathologies

(Country) N of pts Phase

H&N

(Taiwan) 27 I/II

H&N

(Taiwan) 28 I/II

GBM

(Japan) 45 II

Melanoma

(Argentina) 15 I

Improvement in survival rate

Glioblastoma multiforme

Kato et al. Appl Radiat Isot 2009; 67:S37-42 Kawabata et al. Appl Radiat Isot 2009; 67:S15-18

Recurrent head and neck cancer

Operative BNCT centres

Past………………present

1950

• Thermal neutron beams

• Boronated agent (sodium

tretraborate, sodium

pentaborate, sodium

decahydrodecaborate)

• Intra-operative approach

• No accurate dosimetric

assessment

• No BNCT planning

• Mostly brain cancer

Today

• Thermal and Epithermal neutron beams

• Boronated agent (BPA and BSH)

• External irradiation (intra and extra-operative approach)

• Accurate microdometric assessment

• MRI, PET and other device for BNCT planning

• Many solid cancers (brain, melanoma, head and neck, liver, and so on)

Content

• Background

• Boron delivery agents

• Clinical dosimetry

• Treatment planning techniques

• Clinical trials (past and on going)

• Advantages and critical issues

What are some advantages of

BNCT?

1. To selectively deliver a high radiation dose to the tumor with a

much lower dose to surrounding normal tissues

2. To more effectively target multicentric deposits of tumor than is

possible with stereotactic radiosurgery of primary and metastatic

brain tumor

3. To have a great local control, although it is usually employed in

case of large disseminative disease.

4. To produce striking clinical responses

5. To increase the survival period in patients with gliomas if

performed with specific protocol

Critical issues

1. The development of new low and high molecular weight boron

agents and optimization of their delivery

2. To obtain approval for the clinical use

3. To compare and normalize dose descriptions between centers

4. The improvement of methods to determine the boron dose

delivered to the residual tumor volume

5. To complete the neutron therapeutic approach with other

treatments